Atherosclerosis is a long-term chronic inflammatory disease which is associated with increased concentrations of various inflammatory markers, including the hepatic-origin C-reactive peptide (“CRP”) (Zambon et al., 2006). CRP has been identified not only as a very sensitive marker and risk factor for atherosclerosis, but also as a pro-inflammatory mediator which is involved in endothelial cell dysfunction, oxidant stress, and intimal hypertrophy, leading to plaque rupture and myocardial infarction. (Wilson et al., 2006; Mora et al., 2006; Paffen et al., 2006; Inoue, 2006; de Ferranti, et al., 2007; Gotto et al., 2007; Bisoendial et al., 2007; and Gonzalez-Gay, et al., 2005)
Evidence for the direct causal role of CRP in atherosclerosis includes its ability to induce matrix metalloproteinase-1 (“MMP-1”) expression through the Fc gamma RII and extra cellular signal-related kinase pathways (shown in U937 cells). MMP-1, in turn, are implicated in plaque instability. Additionally, CRP is shown to up-regulate interleukin-1, interleukin-6, and interleukin-8 in human aortic endothelial cells via nuclear factor-kappa B. CRP also promotes monocyte chemoattractant protein-1-mediated chemotaxis by up regulating CC-chemokine receptor 2 expression in human monocytes. CRP is also shown to attenuate endothelial progenitor cell survival, differentiation, and function. (Venugopal et al., 2005)
Other proinfiammatory, proatherogenic effects of CRP on endothelial cells include the following: decreased endothelial-derived nitric oxide and prostacyclin versus increased endothelin-1, cell adhesion molecules, monocyte chemoattractant protein-1 and plasminogen activator inhibitor-1 (leading to higher likelihood for a blood clot). In monocyte-macrophages, CRP may induce tissue factor secretion, increase reactive oxygen species and proinflammatory cytokine release, promote monocyte chemotaxis and adhesion, and increase oxidized low-density lipoprotein uptake. Also, CRP has been shown in vascular smooth muscle cells to increase inducible nitric oxide production (thought to be detrimental as opposed to endothelial-derived nitric oxide), increase NFkappa-b and mitogen-activated protein kinase activities, and, importantly, up regulate angiotensin type-1 receptor resulting in increased reactive oxygen species and vascular smooth muscle cell proliferation. (halal et al., 2004; and Chang et al., 2005)
N-acetylcysteine (NAC) is an antioxidant and a thiol donor. Currently, NAC is clinically used for treatment of hepatotoxicity caused by acetaminophen overdose, for treatment of chronic bronchitis and other pulmonary diseases complicated by the production of viscous mucus, and for treatment of reperfusion injury during cardio bypass surgery. The protective effects of NAC against inflammatory/oxidative challenges were also demonstrated in various animal models of brain injury, (Fu et al., 2006; Hicdonmez, et al., 2006; Jara-Prado et al., 2003; Karageorgos, et al., 2006; Penugonda et al., 2005; Price et al., 2006; Shea, 2007; and Tchantchou et al., 2004) liver injury, (Kaya et al., 2008; Liu et al., 2007; and Alipour et al., 2007) and lung injury (e.g. LPS-induced, TNF-mediated MPO increase and apoptosis) (Koksel, et al., 2004; Chuang et al., 2007; and Chen et al., 2007) In vitro, NAC also inhibited the oxidative modification of LDL. (Van Antwerpen et al., 2005) In particular, secondary oxidation of LDL by previously oxidized LDL was markedly inhibited, (Rattan et al., 1998) an effect not seen with other antioxidants. NAC was also shown to reduce the ability of lipid loaded macrophages (foam cells) to degrade vascular matrix. (Galis, et al., 1998)
Several animal models have actually demonstrated inhibition of atherosclerosis by NAC. (Fujii et al., 2006; Krieger et al., 2006; lvanovski et al., 2005; and Wagberg et al., 2001) Based on the data cited above, CRP may be a suitable target for therapy to reduce atherosclerosis. However, currently there is no specific therapy to lower CRP concentration. Although statin therapy, some ACE inhibitors and ARBs, anti-inflammatory drugs, and perhaps fish oils have some benefits, (Prasad et al., 2006; Devarai et al., 2007; and Nissen, 2005) their benefit is limited, and difficult to assess because of their other biochemical effects, and many are associated with undesirable side effects.
In addition to the cell cultures studies (cited above) demonstrating the protective effects on NAC against CRP-mediated inflammation, an immediate release form of NAC has been recently demonstrated to lower CRP serum concentrations. Intravenous NAC was administered to patients undergoing abdominal surgery. CRP level following the surgery fell by 30% as compared to placebo infusion. (Molnar et al., 2003) Even more impressively, Patients with exacerbation of chronic obstructive pulmonary disease (COPD) demonstrated an increase in CRP but orally administered NAC resulted in decreased CRP (CRP normalized in 52% of patients on 600 mg/day and 90% of patients on 600 mg twice a day). The apparent greater efficacy of oral NAC vs. intravenous NAC may be related to the increased liver delivery of NAC via the oral route. (Zuin et al., 2005) Therefore, NAC is a very appealing therapeutic agent for achieving a reduction in CRP, thereby reducing inflammation and oxidative damage, and for the prevention/treatment of atherosclerosis and possibly other inflammatory and/or oxidative insults in other diseases such as Parkinson's disease (note its benefit in MPTP-induced Parkinson's disease and other models). (Penugonda et al., 2005; Aoyama et al., 2007; Shavali et al., 2007; and Kim-Han et al., 2007)